ABSTRACT
The maximum fluxes of 32 prodrugs and parabens through polydimethylsiloxane membranes from water (EXP log J(MPAQ)) have been correlated with the maximum flux of the same prodrugs and parabens through hairless mouse skin from water (EXP log J(MMAQ)): EXP log J(MMAQ)=0.608 EXP log J(MPAQ)-0.636, r(2)=0.743. The average of the absolute values for the differences between the EXP log J(MMAQ) and the log J(MMAQ) calculated from EXP log J(MPAQ) (Delta log J(MMAQ)) was 0.227 log units. Similarly the maximum fluxes of 11 unrelated permeants through human skin from water (EXP log J(MHAQ)) was correlated with the EXP log J(MPAQ) for the same permeants: EXP log J(MHAQ)=0.516 EXP log J(MPAQ)-0.922, r(2)=0.82 and Delta log J(MHAQ)=0.252 log units. Since the best fit of the databases for EXP log J(MPAQ), log J(MMAQ) and log J(MHAQ) was to the Roberts-Sloan (RS) model, and the dependency of RS on a balance in lipid and aqueous solubility for optimization of topical delivery has been established, the present correlation suggests that the flux through a silicone can be used to predict flux through mouse or human and that the physicochemical properties that lead to optimized flux through one membrane will lead to optimized flux through the others.
Subject(s)
Dimethylpolysiloxanes/chemistry , Membranes, Artificial , Models, Biological , Organic Chemicals/chemistry , Organic Chemicals/pharmacokinetics , Skin Absorption/physiology , Skin/metabolism , Algorithms , Animals , Databases, Factual , Humans , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Mice , Mice, Hairless , Parabens/chemistry , Parabens/pharmacokinetics , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Solubility , Water/chemistryABSTRACT
Data for the delivery of total species containing parent drugs from water through hairless mouse skin by prodrugs, logJ(MMAQ), has been fitted to the Roberts-Sloan, RS, the Kasting-Smith-Cooper, KSC, and Magnusson-Anissimov-Cross-Roberts, MACR, equations. The RS model which contains a parameter for the dependence of flux on solubility in water, S(AQ), as well as solubility in the lipid isopropyl myristate, S(IPM), gave the best fit: logJ(MMAQ)=-2.30+0.575 logS(IPM)+0.425 logS(AQ)-0.0016MW, r(2)=0.903. The values for the coefficients to the parameters are quite similar to those obtained when the RS model was fit to flux of solutes from water through human skin, logJ(MHAQ). There was no trend in predicting the under or over-performance of prodrugs based on their fit to the RS model and whether they were more or less soluble than their parent drugs. There was an inverse dependence of logJ(MMAQ) on partition coefficients or permeability coefficients similar to that observed for logJ(MHAQ). The similarities in trends for results for logJ(MMAQ) and logJ(MHAQ) suggests that design directives obtained from mouse skin can be extended to design new prodrugs or select new drugs for delivery through human skin.
Subject(s)
Models, Biological , Prodrugs/pharmacokinetics , Skin Absorption , Animals , Diffusion , Drug Design , Female , Humans , Mice , Mice, Hairless , Myristates/chemistry , Permeability , Prodrugs/chemistry , Skin/metabolism , Solubility , Solvents/chemistryABSTRACT
Neuropsychological impairments punctuate the early neurological involvement among HIV-1 infected patients. Three groups of patients, twenty in each were selected. The first group consisted of seronegative local controls, the second being a group of asymptomatic seropositive patients and the third a group of seropositive symptomatic individuals. All these three groups were tested using standard neuropsychological tests. Results indicate that a broad spectrum of impairments occur in the seropositive patients and that the impairments of various functions occur at different phases of the illness. The importance of these findings in prediction of early neurological disturbance is highlighted and their significance in the total management and rehabilitation is discussed.
